A number of mechanisms have been proposed to explain the depletion of helper CD4+ cells in HIV-infected individuals. This loss may be associated with increase apoptosis. Current studies in our laboratory are directed toward understanding the mechanisms employed by cells undergoing programmed cell death. We have focused on the role of the HIV tat gene in this process. Tat can modulate the redox state of cells by altering the activity of various enzymes to shift the cellular state toward pro-oxidant conditions. We have shown that the altered redox state can cause cells to die by apoptosis. Currently we are studying the regulation of the cell death mediated by the interactions of the tat andTNF-alpha as well as the role of p53 and oxidant stressors in the process. We have generated several cell lines that contain constitutively activated tat. In these cells, tat potentiated TNF- induced activation of the transcription factor, NF-kappa-B, and cellular cytotoxicity. In addition we have shown that TNF-induced toxicity is mediated by the TNFRI. Furthermore, we have shown that addition of recombinant, soluble HIV tat protein could induce TNFRI expression. By increasing TNFRI, tat is able to potentiate the effects of TNF. This is the final year for this project, some components of this project will be continued under a new project # involving cDNA microarrays. - apoptosis, tat, tumor necrosis factor, NF-kappa B, CAPE, oxidative stress